Imaging In Traumatic Brain Injury:What Have We Learned?

A Functional and Molecular Neuroimaging Perspective

Emily Stern, MDDirector, Functional Neuroimaging Laboratory

Director, Functional and Molecular NeuroimagingDepartments of Radiology and Psychiatry

Associate Professor of Radiology

Brigham and Women’s HospitalHarvard Medical School

Disclosures

I have NO RELEVANT financial disclosure

Outline Beyond structure: what can functional and

molecular neuroimaging tell us Introduction to methodologies

TBI and brain function (as assessed by fMRI) Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PET

INTRuST DOD pilot study Additional future directions

Where we need to go Summary

Outline Beyond structure: what can functional and

molecular neuroimaging tell us Introduction to methodologies

TBI and brain function (as assessed by fMRI) Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PET

INTRuST DOD pilot study Additional future directions

Where we need to go Summary

Functional Brain Mapping

Functional Brain Mapping The use of functional magnetic

resonance imaging (fMRI) or positron emission tomography (PET) as a marker of neuronal activity

Can identify focal areas of increased or decreased neuronal activity in different mental conditions or disease states

Can identify areas of dysfunction in the absence of structural change

18F-FDG PET

H215O PET

BOLD fMRI

Arterial Spin Tagging fMRI

BLOOD VOLUME

BLOOD OXYGENATION

11CO PETGadolinium DTPA fMRI

Functional Imaging Method

(PET and fMRI)

fMRI: Measuring BOLD activity at every point in the brain (voxel) over time

HOPELESS

HOPELESS

[Ex. Hopeless]

Types of fMRI Studies Symptom capture (e.g. hallucinations, tics) Activation studies

probe cognitive process and / or neural system of interest for particular disorders

Pre- and post-treatment evaluation Resting state assessment Connectivity analyses

Assess how brain regions function in concert with each other

Can correlate fMRI data directly with: Structural imaging Extensive standardized clinical ratings Neurobehavioral data Genetics

allelic variants/single nucleotide polymorphisms to identify imaging endophenotypes associated with core clinical features, and that can serve as predictors of differential treatment response

Physiological Measures e.g. cortisol, skin conductance response

Eye tracking Intracranial and surface EEG Fluid Biomarkers

Metabolomics, proteomics, lipidomics, immunomics

Skin

Con

duct

ance

Res

pons

e

Ex: Abnormal frontolimbic functionCorrelations between BOLD activity and cortisol change prescan to postscan

(Root et al, Neuroreport, 2009)

Healthy subjects: threatening stimuli

RL

Positron Emission Tomography(PET)

Positron Emission Tomography (PET) A functional, nuclear medicine technique that

allows imaging of cellular and molecular processes

Tag a biologically active molecule with small amount of radioactivity (similar amount to diagnostic radiological test) and observe binding

Choose radiotracer to target particular molecular function of interest (e.g. glucose metabolism; neuroinflammation)

PET Procedurehttp://www.sepscience.com/Sectors/Pharma/Articles/429-/Radio-IC-for-Quality-Control-in-PET-Diagnosticshttp://www.slideshare.net/tmhnehru/handout-rmnlectureapplication-of-radiationinmedicineandresearch30122013http://www.fz-juelich.de/inm/inm-4/EN/Home/_Fokus/Informationen/_node.html

1.

3.2.

4.

Example: 18F-FDG and 11C-PK11195 PETNeuroinflammation in Patient with Epilepsy Due to Focal Cortical Dysplasia

Ictal 18F-FDG PET Interictal 18F-FDG PET 11C-PK11195 PET

(Butler et al, 2011)

R L

Outline Beyond structure: what can functional and molecular

neuroimaging tell us Introduction to methodologies

TBI and brain function (as assessed by fMRI) Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PET

INTRuST DOD pilot study Additional future directions

Where we need to go Summary

fMRI and TBI to date:Activation Study Examples

Majority focused on probing Executive function: comprises multiple

higher order functions including planning, execution, reasoning, working memory, problem solving Spatial planning/”Tower of London”

task in NFL players: hyperactivation and hypoconnectivity dorsolateral frontal and frontopolar; correlated with # of times removed from play (Hampshire et al, 2013)

(Hampshire et al, 2013) Inhibitory function:

Correct inhibitions: increased ACC and OFC; incorrect inhibitions: increased caudate and cerebellum (Fischer et al, 2014)

frontal lobe function, e.g.

fMRI and TBI to date:Activation Study Examples Majority focused on probing frontal lobe function, e.g.

Working memory: system responsible for transient holding and processing of new and already-stored information; important for reasoning, comprehension, learning and memory updating. Caudate dysfunction (decreased activation) during encoding

(Newsome et al 2015; Increased posterior cingulate activation (Wylie et al 2015) Widespread hyperactivation – B visual encoding, B frontoparietal

WM network regions, L temporal during successful encoding (Gillis et al, 2014)

Increased WM load: altered (increased and decreased depending on specific aspect of taskactivation DLPFC and parietal, in 9-15 y.o. (Sinopoli et al 2014)

fMRI and TBI to date:Activation Study Examples What about emotional function?

Emotional dysfunction/psychiatric disease well known sequelae of TBI, e.g. PTSD: prevalence in TBI uncertain (1-50%); 2008 Rand Report: 7%

of troops from Iraq and Afghanistan had TBI with co-morbid PTSD or depression (Tanev et al, 2015)

Other neuropsychiatric disease: depressed mood, anxiety, impulsive/aggressive behavior, sleep disturbance, delerium (Bhalerao et al, 2015)

Many fewer functional neuroimaging studies, e.g. Decreased facial affect recognition with associated decreased

activity in R fusiform gyrus (Neumann et al, 2015) TBI + MDD c/w TBI alone, emotional face matching task: increased

B amygdala, decreased cognitive control regions (DLPFC)(Matthews et al, 2011)

Most fMRI activation studies have focused on frontal lobe function

Findings include abormalities in a range of regions, including frontal, parietal, temporal, subcortical

Variability could be due to differences in activation tasks, chronicity and site of injury

Very few studies to date targeting in other regions or other functions (in particular emotional function)

(Note regarding severe TBI and disorders of consciousness)

fMRI and TBI to date:Activation studies summary

fMRI and TBI to date:Resting State Study Examples

Spontaneous low-frequency fluctuations in BOLD activity result in patterns of correlated activity between brain regions (Biswal et al, 1995)

Can be thought of as the “idling” brain Default mode network (DMN) is well-known example:

medial PFC (TOM), posterior cingulate (integration), precuneus (episodic memory,

self reflection), parietal Medial temporal lobe

(memory)

(Fox et al, 2005)

Large number of recent studies, esp mild TBI: Increased FC between sub-thalamic regions and sensory cortical

regions and DMN, [<10d post TBI] (Sours et al, 2015) Increased FC in regions of the DMN and between cerebellum and

SMA; [<1 yr post TBI] (Nathan et al, 2015) Decreased FC in bilat somatosensory and motor cortices, but only

when proximal to blast (<10m), [<1yr-~5yr post deployment] (Robinson et al, 2015)

Veterans with TBI and increased re-experiencing PTSD sxs: decreased FC in network engaged in gating of working memory, [time post TBI NA] (Spielberg et al, 2015).

Possible reasons for variability: differences in chronicity; differences in sites of injury

fMRI and TBI to date:Resting State Study Examples

Outline Beyond structure: what can functional and molecular

neuroimaging tell us Introduction to methodologies

TBI and brain function (as assessed by fMRI) Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PET

INTRuST DOD pilot study Additional future directions

Where we need to go Summary

DOD INTRuSt ConsortiumINjury and TRaumatic STress

Novel Functional and Structural Biomarkers of Neuroinflammation and White Matter Change

in TBI: a Potential New Diagnostic and Therapeutic Approach

M. Shenton, PhD E. Stern, MDR. Zafonte, DO

The role of neuroinflammation in TBI Rationale

In addition to better understanding the pathophysiology underlying the phenotype (fMRI), it is critical to address the molecular processes that occur after TBI

Prerequisite for developing new treatment targets

The role of neuroinflammation in TBI

AimIdentification of novel neuroinflammatory and white matter biomarkers of TBIBackground Mild TBI: difficult to predict which pts will go on to have

persistent cognitive/emotional sxs Therefore important to examine pathophysiological

processes that occur subsequent to injury Evolving belief that pathophysiological changes after TBI

include significant inflammatory and immunological components

Microglia and the TSPO protein Microglia are brain’s resident immune cell: become activated almost immediately

after injury; can be chronically activated; Serve as major antigen-presenting cells in brain, phagocytosis/clearance: crucial for

neuroinflammatory cascade; sythesize immune mediators (cytokines, chemokines, complement activation proteins)

PET radioligand [11C]-PK11195 binds to TSPO (translocator) protein expressed on mitochondria of activated microglia sensitive to neuroinflammation

Concept of harmful vs. beneficial inflammation (Neurotoxic vs. neuroprotective )

Prolonged microglial activation may lead to excessive, poorly-reglulated inflammation and can be cytotoxic (Gentleman et al, 2004; Bal-Price et al, 2001)

Evidence for time-dependent role for different microglial phenotypes (Febinger et al, 2015)

Implications: Anti-inflammatory treatment At time of trauma; longer term; prophylactically?

The role of neuroinflammation in TBIBackground (continued)

The role of neuroinflammation in TBI Hypotheses Acutely, will observe inflammatory changes 1-2 weeks post

TBI with 11C-PK11195 PET, particularly in region of injury

Pts with greater inflammation, DAI, and micro-hemorrahagic changes at 1-2 wks will show greater impairment on neuropsychological measures at 3 months

Chronically, at 3 months, inflammatory change will be present, in different pattern than acute changes, reflecting secondary microglial activity in sites adjacent to and more distally connected to original site of injury, due to remodeling, Wallerian degeneration, etc.

The role of neuroinflammation in TBI Methods

Imaging: PET with [11C]-PK11195:

novel translocator (TSPO) protein receptor ligand binds to mitochondria of activated microglia in the brain marker of neuroinflammation

Structural MRI, diffusion tensor imaging (DTI) and Susceptibility Weighted Imaging (SWI) also obtained

Timing of measurements: 1-2 weeks post TBI and 3 months post TBI Based on animal literature for neuroinflammation in TBI

and human literature for neuroinflammation in stroke (with PK1195)

Unpublished data removed

Outline Beyond structure: what can functional and molecular

neuroimaging tell us Introduction to methodologies

TBI and brain function (as assessed by fMRI) Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PET

INTRuST DOD pilot study Additional future directions

Where we need to go Summary

Functional and Molecular Neuroimaging in TBI: Next steps to keep in mind for the field

More extensive examination of biological aspects of brain function after TBI based upon Clinical phenotypes

Take advantage of what we know about cognitive and emotional (including psychiatric dysfunction) to probe additional brain areas and brain structures with fMRI

(b) to panic related words controlled for neutral words, over time (early vs late)

(a) to PTSD related words controlled for neutral words, over time (early vs late)

(y= -3) p<0.01.

(Protopopescu et al, Biol Psych 2005)

Example: Abnormal Frontolimbic Function Amygdala response in PTSD vs NL subjects

Time and stimulus specificity

Functional and Molecular Neuroimaging in TBI: Next steps to keep in mind for the field

More extensive examination of biological aspects of brain function after TBI: Incorporate additional information into our

models Genotype (imaging can act as an “endophenotype”) Proteomics, metabolomics, immunomics, etc.

Better stratify studies based upon severity and chronicity

Translational approach Integration of different

imaging modalities Conduct studies pre- and

post-intervention

Functional and Molecular Neuroimaging in TBI: Next steps to keep in mind for the field

•Scanning before treatment•Patterns of brain activity that correlate with/predict treatment response

•Scanning after treatment•Patterns of brain activity that correlate with successful treatment

•Post- vs. Pretreatment scans•Changes in patterns of brain activity associated with treatment response

Outline Beyond structure: what can functional and molecular

neuroimaging tell us Introduction to methodologies

TBI and brain function (as assessed by fMRI) Where we are: frontal lobe function, resting state

TBI pathophysiology: the role of neuroinflammation as assessed by PET

INTRuST DOD pilot study Additional future directions

Where we need to go Summary

Summary and Conclusions fMRI is a powerful tool to examine brain function after TBI, though has not

been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.

Molecular processes that occur after injury, such as inflammation, can be examined in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the field,including incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-tx.

Summary and Conclusions fMRI is a powerful tool to examine brain function after TBI, though has not

been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.

Molecular processes that occur after injury, such as inflammation, can be examined in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the field,including incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-tx.

Summary and Conclusions fMRI is a powerful tool to examine brain function after TBI, though has not

been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.

Molecular processes that occur after injury, such as inflammation, can be examined in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the field,including incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-tx.

Summary and Conclusions fMRI is a powerful tool to examine brain function after TBI, though has not

been used extensively yet. While most work to date has focused on working memory and the resting state, future work should be tied to the broader range of clinical phenotypes that exist after TBI.

Molecular processes that occur after injury, such as inflammation, can be examined in vivo with PET. These may be particularly important for determining novel interventions.

There are a number of ways to advance the field,including incorporating additional sources of information(e.g. genotyping, proteomics, etc.), further integrating the results of different imaging modalities, and imaging pre- and post-tx.

Citations1. Bal-Price, A. and G.C. Brown, Inflammatory neurodegeneration mediated by nitric oxide from activated glia-

inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci., 2001. 21(17): p. 6480-91.

2. Bhalerao, S.U., et al., Understanding the neuropsychiatric consequences associated with significant traumatic brain injury. Brain Inj, 2013. 27(7-8): p. 767-74. doi: 10.3109/02699052.2013.793396.

3. Biswal, B., et al., Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med., 1995. 34(4): p. 537-41.

4. Butler, T., et al., Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. J Neuroimaging., 2013. 23(1): p. 129-31. doi: 10.1111/j.1552-6569.2010.00572.x. Epub 2011 Jan 11.

5. Febinger, H.Y., et al., Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury. J Neuroinflammation., 2015. 12(1): p. 154. doi: 10.1186/s12974-015-0386-5.

6. Fischer, B.L., et al., Default mode network interference in mild traumatic brain injury - a pilot resting state study. J Neurotrauma., 2014. 31(2): p. 169-79. doi: 10.1089/neu.2013.2877. Epub 2013 Nov 1.

7. Fox, M.D., et al., The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A., 2005. 102(27): p. 9673-8. Epub 2005 Jun 23.

8. Gentleman, S.M., et al., Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci Int., 2004. 146(2-3): p. 97-104.

9. Gillis, M.M. and B.M. Hampstead, Close-range blast exposure is associated with altered functional connectivity in Veterans independent of concussion symptoms at time of exposure. Brain Imaging Behav, 2014. 7: p. 7.

Citations10. Matthews, S.C., et al., A multimodal imaging study in U.S. veterans of Operations Iraqi and Enduring

Freedom with and without major depression after blast-related concussion. Neuroimage., 2011. 54(Suppl 1): p. S69-75. doi: 10.1016/j.neuroimage.2010.04.269. Epub 2010 May 6.

11. Nathan, D.E., et al., Imaging brain plasticity after trauma. Brain Connect., 2015. 5(2): p. 102-14. doi: 10.1089/brain.2014.0273. Epub 2014 Dec 22.

12. Neumann, D., et al., Cognitive Improvement after Mild Traumatic Brain Injury Measured with Functional Neuroimaging during the Acute Period. Brain Imaging Behav, 2015. 4: p. 4.

13. Neumann, D., et al., Neurobiological mechanisms associated with facial affect recognition deficits after traumatic brain injury. Brain Imaging Behav, 2015. 4: p. 4.

14. Newsome, M.R., et al., Neurobiological mechanisms associated with facial affect recognition deficits after traumatic brain injury. Neuroimage Clin., 2015. 8:543-53.(doi): p. 10.1016/j.nicl.2015.04.024. eCollection 2015.

15. Protopopescu, X., et al., Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry., 2005. 57(5): p. 464-73.

16. Robinson, M.E., et al., Exploring variations in functional connectivity of the resting state default mode network in mild traumatic brain injury. Hum Brain Mapp., 2015. 36(3): p. 911-22. doi: 10.1002/hbm.22675. Epub 2014 Nov 4.

17. Root, J.C., et al., Frontolimbic function and cortisol reactivity in response to emotional stimuli. Neuroreport., 2009. 20(4): p. 429-34. doi: 10.1097/WNR.0b013e328326a031.

Citations18. Sinopoli, K.J., et al., Imaging "brain strain" in youth athletes with mild traumatic brain injury during

dual-task performance. J Neurotrauma., 2014. 31(22): p. 1843-59. doi: 10.1089/neu.2014.3326. Epub 2014 Sep 11.

19. Sinopoli, K.J., et al., Serum Neuron-Specific Enolase Is Related to Cerebellar Connectivity: A Resting-State Functional Magnetic Resonance Imaging Pilot Study. J Neurotrauma., 2014. 31(22): p. 1843-59. doi: 10.1089/neu.2014.3326. Epub 2014 Sep 11.

20. Sours, C., et al., Hyper-connectivity of the thalamus during early stages following mild traumatic brain injury. Brain Imaging Behav., 2015. 9(3): p. 550-63. doi: 10.1007/s11682-015-9424-2.

21. Sours, C., et al., Chronology and chronicity of altered resting-state functional connectivity after traumatic brain injury. Brain Imaging Behav., 2015. 9(2): p. 353-4. doi: 10.1007/s11682-014-9310-3.

22. Spielberg, J.M., et al., Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans. Biol Psychiatry., 2015. 78(3): p. 210-6. doi: 10.1016/j.biopsych.2015.02.013. Epub 2015 Feb 18.

23. Tanev, K.S., et al., PTSD and TBI co-morbidity: scope, clinical presentation and treatment options. Brain Inj, 2014. 28(3): p. 261-70. doi: 10.3109/02699052.2013.873821.

24. Wilde, E.A., et al., Advanced neuroimaging applied to veterans and service personnel with traumatic brain injury: state of the art and potential benefits. Brain Imaging Behav, 2015. 8: p. 8.

25. Wylie, G.R., et al., Sex differences in orbitofrontal connectivity in male and female veterans with TBI. PLoS One., 2015. 10(5): p. e0126110. doi: 10.1371/journal.pone.0126110. eCollection 2015

Acknowledgements BWH Functional

Neuroimaging Laboratory (FNL)

David Silbersweig, MD Hong Pan, PhD Lorene Leung Rachel Cohn Monica Bennett Ben Coiner Jane Epstein, MD Andrea Field

BWH Psychiatry Neuroimaging Laboratory

Martha Shenton, PhD Michael Coleman Wonderful RAs!

Spaulding RH Ross Zafonte, DO

BWH Nuclear Medicine Marie Kijewksi, PhD Mi-Ae Park, PhD

Funding :ForTBI PET Neuroinflammation: INTRuST Consortium/DODOther current funding: NIDRR, Epilepsy Foundation, NFL Players Association, Garden Fund, Northeastern University, Gilead Pharmaceutical, Merck Pharmaceutical

BWH Neurology/FNL Tarun Singhal, MD

Thank you!estern3@partners.ortg

www.functionalneuroimaginglab.org